HIV-1 Signalling Remodels Nuclear Pores to Licence Infection in Resting T Cells
Human Immunodeficiency Virus type 1 (HIV-1) continues to challenge the scientific and medical communities due to its complex mechanisms of infection and persistence. Resting CD4+ T cells, which constitute the majority of T cells in the human body, have long been considered largely resistant to HIV-1 infection. Traditionally, it was thought that T cell activation was a prerequisite for successful viral invasion and integration. However, recent groundbreaking research uncovers a sophisticated viral strategy that HIV-1 employs, fundamentally altering this understanding by elucidating how viral signalling remodels nuclear pore complexes (NPCs) to license infection even in resting T cells.
The HIV-1 capsid—essential for transporting the viral genome—must traverse the nuclear envelope through NPCs to deliver the viral DNA into the host nucleus, an indispensable step for viral integration and productive infection. The new study reveals that resting T cells inherently resist HIV-1 infection primarily because capsid nuclear import is inefficient. The nuclear envelope, a vital barrier punctuated by NPCs, tightly controls macromolecular trafficking between cytoplasm and nucleus. This barrier prevents the viral capsid from efficiently entering the nucleus, thus safeguarding resting T cells against infection.
Remarkably, HIV-1 overcomes this barrier through a mechanism involving cell-to-cell spread (CCS). Unlike cell-free viruses, direct contact between infected and uninfected T cells triggers CD4 receptor-mediated signalling cascades, notably involving the tyrosine kinase LCK and subsequent activation of cyclin-dependent kinase 1 (CDK1). This intracellular signalling remodels the architecture and function of nuclear pore complexes, enhancing their permeability or affinity for the viral capsid. These changes permit more rapid and efficient capsid nuclear import, thus licensing successful infection even in resting cells previously considered refractory.
Activated T cells are highly permissive to HIV-1 infection, consistent with decades of research showing that T cell activation enhances intracellular viral processes. Yet in vivo, the majority of T cells remain in a resting state. It has been contentious how infected resting T cells arise, with assumptions focusing on their prior activation and subsequent return to resting quiescence. The present findings suggest that direct CD4–LCK signalling at the virological synapse during CCS plays a pivotal role. By activating CDK1, this signalling remodels NPC components at a post-translational level, effectively transforming the nuclear entry gateway and broadening HIV-1’s infectious potential.
Central to this process is the remodeling of NPCs, intricate macromolecular structures constructed from over 30 nucleoporins forming a selective channel of approximately 120 megadaltons. Previous views emphasized select nucleoporins that directly interact with HIV-1 capsid as co-factors for infection. However, the study proposes a paradigm shift in which the entire NPC complex acts as a viral co-factor, dynamically adapting in response to HIV-1-induced signals. Remodeling events not only facilitate viral nuclear import but may also reshape host cell nuclear transport, influencing gene expression patterns.
The kinase CDK1, historically recognized for orchestrating mitotic entry, emerges as a crucial effector driving NPC phosphorylation and architectural remodeling. The study details widespread CDK1-dependent phosphorylation changes across cytoplasmic, central channel, and nuclear basket nucleoporins, including key components Nup54, Nup62, and TPR. These modifications alter the positioning and interaction potential of nucleoporins, potentially increasing NPC permeability or altering receptor-mediated transport to favor capsid translocation. This mechanistic insight fills vital gaps in understanding how HIV-1 negotiates the NPC barrier.
The authors observe enriched puncta of nucleoporins Nup54, Nup62, and TPR in association with incoming viral capsids, hinting at either the reorganization of existing nuclear pores or the assembly of nascent NPCs to facilitate capsid passage. While the exact ultrastructural ramifications remain unresolved, these findings emphasize dynamic nuclear pore plasticity in immune cells and raise questions about how environmental stimuli or immune activation cues sculpt NPC architecture.
Intriguingly, the study extends beyond virology to touch upon broader immunological implications. Co-stimulatory receptor CD4, classically appraised as an amplifier of antigen-specific T cell receptor (TCR) signalling, may directly activate LCK independently, thereby modulating CDK1 activity and nuclear transport even in the absence of canonical TCR engagement. This suggests that CD4 signalling imparts discrete regulatory capacities influencing T cell functional states, broadening the conceptual framework of peripheral T cell responses.
Given CD4’s expression on other immune populations lacking TCR—for example, macrophages and dendritic cells—this signalling axis might represent a more general mechanism tuning immune cell nuclear dynamics and function. Understanding this may inform new avenues for immunotherapy, harnessing co-stimulatory signalling pathways to fine-tune immune responses and develop tailored interventions.
Additionally, the enhanced nuclear import machinery may impact HIV-1 integration site selection and viral persistence. Nucleoporins influence chromatin organization proximal to nuclear pores, and signalling-induced NPC rearrangement may govern where HIV-1 inserts into the host genome. As integration sites affect viral transcriptional activity and immune recognition, this could have profound consequences for HIV-1 latency and pathogenesis.
The study’s focus on the juxtaposition of fine molecular signalling, nuclear pore remodeling, and viral nuclear import extends its significance. It highlights how localized extracellular interactions at the virological synapse cascade inward to modify host cellular architecture at the nuclear envelope, dramatically shifting the intracellular landscape to promote viral replication.
This paradigm also elucidates why cell–cell spread is significantly more efficient than cell-free infection. By promoting simultaneous viral transfer and host cell signalling that overcomes intrinsic nuclear entry restrictions, HIV-1 ensures robust infection of resting T cells in vivo. These discoveries thus redefine the interplay between viral transmission modes, host cell signalling pathways, and nuclear transport systems in HIV-1 pathogenesis.
Future research into other viruses that must traverse the NPC barrier—such as hepatitis B and herpesviruses—may uncover analogous strategies involving manipulation of nuclear pore dynamics and targeted signalling. This work serves as a foundational framework for exploring viral cooption of nuclear transport regulation, potentially revealing universal pathogen tactics.
Conclusively, the confluence of HIV-1 envelope engagement, CD4 receptor signalling, LCK activation, and CDK1-driven nuclear pore remodeling delineates a viral strategy finely tuned to circumvent cellular barriers in resting T cells. These insights advance our molecular understanding of viral-host interactions and open new therapeutic possibilities aiming to disrupt these essential viral processes, offering hope for improved management of HIV-1 infection and its immunological consequences.
Subject of Research: HIV-1 nuclear entry mechanisms and host cell nuclear pore complex remodeling
Article Title: HIV-1 signalling remodels nuclear pores to licence infection
Article References:
Mesner, D., Whelan, M.V.X., Shivkumar, M. et al. HIV-1 signalling remodels nuclear pores to licence infection. Nature (2026). https://doi.org/10.1038/s41586-026-10453-3
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41586-026-10453-3
Tags: HIV-1 capsid nuclear importHIV-1 host cell interactionHIV-1 infection in resting CD4+ T cellsHIV-1 nuclear pore remodelingHIV-1 replication cycle in non-activated T cellsHIV-1 viral signalling pathwaysimmune evasion strategies of HIV-1molecular mechanisms of HIV nuclear entrynuclear envelope and viral integrationnuclear pore complex alterations by HIVresting T cell resistance to HIVviral genome transport mechanisms
